Recent results from the Silva laboratory show that mice with a targeted disruption of the cAMP. -responsive-element binding protein (CREB) gene (CREB-/-) have normal short-term, but deficient long-term responsive- element binding protein (CREB) gene (CREB-/-) have normal short-term, but deficient long-term memory. This behavioral phenotype is paralleled by deficits in hippocampal CA1 long-term potentiation (LTP). The principal objective of this proposal is to determine how CREB modulates short and long-term changes in the physiology of hippocampal CA1 neurons and how these changes may affect behavior. Extracellular and whole-cell recording methods will be used to examine LTP and long-term depression in hippocampal brain slices prepared from CREB mutant mice. I will test the hypothesis that different protocols for LTP induction and fear conditioning can alleviate the deficits of the mutants. Pharmacological treatments which a) modulate the cAMP pathway and b) inhibit protein synthesis, will allow me to determine if the CREB mutation has an impact on biochemical pathways which may be modulating neuronal plasticity. The use of whole-cell recording methods will allow a detailed examination of the electrophysiology of the mutant cells including a comparison of the intrinsic membrane properties and the characteristics of action potentials in WT and mutant neurons. Whole-cell recordings will also be used to determine whether synaptic currents are altered in CREB mutant neurons. Findings in Aplysia, Drosophila and mice indicate that the cellular mechanisms involving CREB in memory are evolutionarily conserved. Thus, the experiments proposed here will have an impact on tahe understanding of cellular mechanisms supporting human memory.